2. Academic Validation
  3. Amidoxime prodrugs convert to potent cell-active multimodal inhibitors of the dengue virus protease

Amidoxime prodrugs convert to potent cell-active multimodal inhibitors of the dengue virus protease

  • Eur J Med Chem. 2021 Nov 15;224:113695. doi: 10.1016/j.ejmech.2021.113695.
Crystall Swarbrick 1,  Vasiliki Zogali 2,  Kitti Wing Ki Chan 3,  Dimitrios Kiousis 2,  Chin Piaw Gwee 4,  Sai Wang 3,  Julien Lescar 5,  Dahai Luo 6,  Mark von Itzstein 7,  Minos-Timotheos Matsoukas 8,  George Panagiotakopoulos 9,  Subhash G Vasudevan 10,  Gerasimos Rassias 11
Affiliations

Affiliations

  • 1 Programm in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road 169857, Singapore; Institute for Glycomics, Griffith University, Gold Coast Campus, QLD, 4222, Australia.
  • 2 Department of Chemistry, University of Patras, Patra, 26504, Greece.
  • 3 Programm in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road 169857, Singapore.
  • 4 Programm in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road 169857, Singapore; Department of Microbiology and Immunology, National University of Singapore, 5 Science Drive 2, 117545, Singapore.
  • 5 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore.
  • 6 Lee Kong Chian School of Medicine, Nanyang Technological University, Experimental Medicine Building, 59 Nanyang Drive, 636921, Singapore.
  • 7 Institute for Glycomics, Griffith University, Gold Coast Campus, QLD, 4222, Australia.
  • 8 Department of Pharmacy, University of Patras, Patra, 26504, Greece.
  • 9 School of Medicine, University of Patras, Patra, 26504, Greece.
  • 10 Programm in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road 169857, Singapore; Institute for Glycomics, Griffith University, Gold Coast Campus, QLD, 4222, Australia; Department of Microbiology and Immunology, National University of Singapore, 5 Science Drive 2, 117545, Singapore. Electronic address: subhash.vasudevan@duke-nus.edu.sg.
  • 11 Department of Chemistry, University of Patras, Patra, 26504, Greece. Electronic address: rassiasg@upatras.gr.
PMID: 34298282 DOI: 10.1016/j.ejmech.2021.113695
Abstract

The Flavivirus genus of the Flaviviridae family comprises Dengue, Zika and West-Nile viruses which constitute unmet medical needs as neither appropriate antivirals nor safe vaccines are available. The dengue NS2BNS3 Protease is one of the most promising validated targets for developing a dengue treatment however reported Protease Inhibitors suffer from toxicity and cellular inefficacy. Here we report SAR on our previously reported Zika-active carbazole scaffold, culminating prodrug compound SP-471P (EC50 1.10 μM, CC50 > 100 μM) that generates SP-471; one of the most potent, non-cytotoxic and cell-active Protease Inhibitors described in the dengue literature. In cell-based assays, SP-471P leads to inhibition of viral RNA replication and complete abolishment of infective viral particle production even when administered 6 h post-infection. Mechanistically, SP-471 appears to inhibit both normal intermolecular Protease processes and intramolecular cleavage events at the NS2BNS3 junction, as well as at NS3 internal sites, all critical for virus replication. These render SP-471 a unique to date multimodal inhibitor of the dengue Protease.

Keywords

Amidines; Amidoximes; Antiviral agents; Dengue and flaviviruses; Multimodal allosteric inhibitors; NS3 internal cleavage; Prodrugs; Structure-activity relationships; Viral protease NS2BNS3.

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